1. Field of the Invention
The present invention relates to a radiopharmaceutical solution comprising 224Ra and a complex capable of scavenging 212Pb and/or 212Bi. This solution can be used for medical purposes, including treatment of cancer. Further aspects of the invention relates to kits and methods for providing specific solutions.
2. Description of the Related Art
Targeted alpha particle radionuclide therapy holds promise as therapeutic modality against malignant and non-malignant diseases. Alpha-emitting radionuclides are highly cytotoxic and the alpha particles produced are of high linear energy, which is delivering a high amount of ionization over a short range, causing destruction of DNA by a high degree of irreparable double strand breaks.
Thus, it is important when using alpha emitting radionuclides that they do reach the target and are not released from the targeting compound and that they do not produce longer lived daughter nuclides that diffuse away from the mother nuclide, since this can cause toxicity in remote tissues.
There are relatively few alpha emitters considered for medical applications. It is a challenge in the field to find a radionuclide with appropriate half life, decay properties, chemical properties and daughter products that are suitable for development of medical treatments.
Radium was very important for the development of radiochemistry sciences and was also used by the pioneers of radio-oncology to treat cancer with brachytherapy (, that is radiation emitting needles or seeds placed within or nearby tumors. Initially 226Ra with a half life (t1/2) of 1600 years was used. Later on 224Ra (t1/2=3.66 days), as dissolved radium chloride injectates, was used for several decades in Germany for the palliative treatment of ankylosing spondylitis (AS) because of the natural bone-seeking property of this, the heaviest of the alkaline earth elements.
Although reintroduced after the development of improved purification methods for a brief period about year 2000, its use was finally abandoned partly due to fear of late effects and the appearance of new treatment options for AS. Therefore 224Ra is not in use as a radiopharmaceutical today and is not considered among the plausible candidates for alpha therapy by leading experts in the field.
There is, however, research going on using 224Ra loaded wires for local intratumoral brachytherapy/radon diffusion therapy but they are not using aqueous 224Ra solutions for therapy.
Recently, another radium isotope, 223Ra, in the form of a dissolved salt injectate, has been granted market authorization as a treatment against skeletal metastases from castration resistant prostate cancer.
When comparing 223Ra (t1/2=11.4 days) with 224Ra (t1/2=3.6 days) both have, in principal, relevant half-lives for radiopharmaceutical uses allowing centralized production and shipment to the end user and both have three alpha emitting progenies in their decay chains and the series are producing a similar amount of alpha particles (FIGS. 1 and 2) with total alpha energy of about 26-28 MeV for the respective chains.
When comparing the decay chains, 223Ra progenies of the Rn, Pb and Bi elements have significant shorter half lives reducing the problem of daughter nuclide uptake in non-target cells and tissues. These differences are particularly important for the lead progenies as these can accumulate in hematopoietic cells and tissues and in kidneys, respectively. In the 223Ra series 211Pb (t1/2=36.1 min) would cause much less normal tissue exposure compared with 212Pb (t1/2=10.6 hours) from the 224Ra series. Unless 224Ra is purified from 212Pb, short before injection, 223Ra would have significantly less normal tissue exposure from progenies. Such purification is impractical since it would require laborious procedures to be performed at the hospital where the product is being used or that the production and use is being geographically restricted. That is why the time frame for use of 224Ra that was previously supplied by Altmann Terapie, Salzgitter, Germany, for AS, was of only 6 hours. It could be used 3 hours before or three hours after the calibration time point. Probably to a significant extent because of this short product shelf life (in addition to increased competition with the new drugs for AS) and the thereby logistics and supply constraint the product has been discontinued.
As of currently, there is no use of 224Ra solution for injection to patients. Instead, there is in development ion exchanger based 224Ra generators for the extraction of 212Pb for the use of 212Pb in radioimmunotherapy. Lead-212 is itself a beta-emitter but decays to the alpha-emitter 212Bi and is therefore considered suitable as an in vivo generator for alpha particle therapy.
Thus, currently 224Ra is considered merely as a generator nuclide for the medically useful 212Pb. Because of the relatively short half life of 212Pb it is expected to be best suited in treatment against compartmental disease where the radioimmunoconjugate is injected directly into the region, e.g., intraperitoneal (i.p.) cavity where a high concentration of product may target malignant ascites and micrometastases within the cavity. The half life of 10.6 hours of 212Pb may be of benefit as only low amount leaks out from the i.p. cavity before the radioactivity has decayed.
When considering radium for therapy against bone diseases, it should be kept in a cationic state since this will ensure that that radium, as the so called “volume-seeker” it is, will be built into the bone minerals causing retention of the daughter nuclides. This is particularly important with 224Ra since some of the daughter nuclides, in particular 212Pb, have substantial half-lives allowing trans-organ redistribution if let free in physiological liquids like blood, saliva or lymphatic liquid. Table 1 (FIG. 4) lists the main radiation of the decay chain of 224Ra.
A monograph about the use of 224Ra in ankylosing spondylitis were developed by the German health authorities about 10 years ago when Altmann Terapie (Salzgitter, Germany) made an effort to re-introduce 224Ra solution as a treatment against ankylosing spondylitis based on a patented production method yielding a highly purified product.
In the decay chain of 224Ra the daughter product 212Pb (t1/2=10.6 hours) is produced. It has a different biodistribution compared to the 224Ra mother nuclide when co-injected in patients. This causes less initial activity in the target tissues and more activity in the non-target tissues like blood cells, in particular hematopoietic cells and tissues, and bone marrow and kidneys. The number of 212Pb atoms compared with 224Ra in a product in radioactive equilibrium is less than 14%. But because 224Ra rapidly transfer from blood to the skeleton or is excreted and 212Pb is substantially retained in hematopoietic cells and tissues, the toxicological impact of 212Bi is important. The only way to solve this problem by current knowledge in the field would be to use 224Ra short time after purification as suggested, that is, before a significant in-growth of 212Pb has taken place.
The use of scavenger for daughter products in experimental radiopharmaceutical research has been described: Jones et al (1996) studied oral administration over several days of the non-targeted dithiol chelating agents 2,3-dimercapto-1-propanesulfonic acid (DMPS) and meso-2,3-dimercaptosuccinic acid (DMSA) to improve the clearance of 206Bi from kidneys in mice and found improved kidney clearance with DMPS. Their aim was to use oral chelate as potential adjuvants to reduce or prevent radiotoxicity in anti-interleukin-2 receptor (IL-2R) 212Pb or 212Bi alpha-radioimmunotherapy. Jaggi et al., (2005) used oral chelation therapy to reduce renal accumulation of 213Bi produced from 225Ac. Their goal was to increase excretion of the undesired daughter product. They did not add the chelator to the radiopharmaceutical but merely describe its use as oral medication in the drinking water before and after injection of radiopharmaceutical.
In terms of bone therapy, 223Ra is considered more appropriate than 224Ra because 223Ra have daughter nuclides with much shorter half-lives and thus, less problem of relocalization. Radium-223 has recently been approved for the therapy of patients with hormone refractory skeletal metastases from prostate cancer.
Dissolved 224Ra salt has previously been tested in cancer therapy but was abandoned because of unfavorable properties and ineffectiveness. It was stated that because of the short half life of 224Ra and its injected daughters, the soft tissue(s) are irradiated. In other words in the case of 224Ra the half life of the daughters, in particular 212Pb, are relatively long compared to the mother nuclides and more soft tissue exposure occurs. Therefore it is known in the field that 224Ra has unfavorable daughter nuclide restricting its use in radiopharmaceutical solutions. Also, in recent review by senior experts in the field, 224Ra was not listed among the candidate radionuclides considered for alpha particle emitter radiopharmaceutical therapy.
The concept of circulating tumor cells (CTC) has lately received considerable attention as CTC may play a critical role in the development of tumor metastases. It is known that cancers that produce skeletal metastases like e.g., prostate-, breast-, lung- and multiple myeloma cancers may have a few viable circulating cancer cells in the blood which may have been shed from the primary or metastatic tumors. This means that even if the bone metastases are treated new lesions can be formed by the settlement of CTC's in the bone or other tissues.
Radium-223 used against bone metastases today is a pure bone-seeker and do not address the problem of CTC's. Therefore there is a need in the field of alpha pharmaceutical bone therapeutics of a product that can also address CTC's.
The generation of daughter nuclides both in the injectates and in vivo is a potential problem for 224Ra and to a lesser extent 223Ra as the first progeny in the two decay series for both is radon which is highly diffusive. However literature data indicate that this is less of a problem when generated in vivo since radium is a bone volume-seeker and is embedded in the bone matrix. It also helps out that the uptake in skeleton of intravenous radium occurs almost instantly and intestinal, and to a less degree urinary, elimination happens rapidly, leading to an elimination from the blood within minutes after injection. It should be mentioned that urinary elimination is probably more pronounced in rodents compared to humans were fecal elimination is the main route. As reported by Nilsson et al (2005), a reduction of 88% of radium in blood at 10 minutes after injection occurs. When considering radium localized in the skeleton, it was for 223Ra reported equilibrium of 211Bi and 223Ra in bone after a few hours. For 224Ra based on animal data and extrapolation to adult human, it was found by two different models a 212Pb to 224Ra fraction of 0.88 and 1.0, i.e., almost complete retention of daughters. These data indicates a high retention of the daughter nuclides in bone for both 223Ra and 224Ra. For 224Ra a significant contribution to soft tissue uptake of progeny would therefore likely be from co-injected daughter nuclide. Thus it is imperative to develop methods to control daughter nuclides, at least 212Pb, in 224Ra injectates.
This has been achieved by the new 224Ra solutions described herein.